Honokiol ameliorates cisplatin-induced acute kidney injury via inhibition of mitochondrial fission. - GreenMedInfo Summary
Honokiol ameliorates cisplatin-induced acute kidney injury via inhibition of mitochondrial fission.
Br J Pharmacol. 2022 Mar 16. Epub 2022 Mar 16. PMID: 35297042
Rui-Wen Mao
BACKGROUND AND PURPOSE: Mitochondrial damage and oxidative stress are the crucial contributors to the tubular cell injury and death in acute kidney injury (AKI). Novel therapeutic strategies targeting mitochondria protection and halting the progression of AKI are urgently needed. Honokiol (HKL) is a small-molecule polyphenol that exhibits extraordinary cytoprotective effects, such as anti-inflammatory and anti-oxidative properties. Thus, we wonder whether HKL could ameliorate cisplatin-induced AKI via preventing mitochondrial dysfunction.
EXPERIMENTAL APPROACH: AKI was induced by cisplatin administration. Biochemical and histological analysis were applied to determine kidney injury. The effect of HKL on mitochondrial function and morphology were evaluated by immunohistochemistry, transmission electron microscopy, immunoblot and immunofluorescence. To investigate the mechanism of HKL in mitochondrial dynamics remodeling and resistance to apoptosis, we did transfection experiments, immunoblot, immunoprecipitation and flow cytometry assay.
KEY RESULTS: We demonstrated that the prominent mitochondrial fragmentation occurred in experimental models of cisplatin-induced nephrotoxicity, which was coupled with radical oxygen species (ROS) overproduction, deterioration of mitochondrial function, release of apoptogenic factors, and consequent apoptosis. HKL treatment exhibited notable renoprotection and attenuated these perturbations. Mechanically, we show that HKL treatment recovered the expression of SIRT3 and improved AMPK activity in tubular cells exposure to cisplatin, which preserved the Drp1 phosphorylation at Ser637 and blocked its translocation to mitochondria, consequently preventing mitochondrial fragmentation and subsequent cell injury and death.
CONCLUSIONS AND IMPLICATIONS: Our results indicate that HKL may protect against cisplatin-induced AKI by preserving mitochondrial integrity and fitness through a mechanism of SIRT3/AMPK-dependent mitochondrial dynamics remodeling.